By R. Tufail. Cleveland Chiropractic College.
Most large axons lose their myelin sheaths and perineurium before reaching the papillary layer of the dermis discount meldonium 500 mg free shipping, with the exception of the axons innervating Merkel cells order meldonium 250mg, although those also become unmyelinated before penetrating the epidermis (Iggo and Muir 1969; Kruger et al. Cauna (1973) described an elaborate cluster of unmyelinated ﬁbers entering the papillary layer of human hairy skin as a free "penicillate ending". Terminals that penetrate the epidermis for a con- siderable distance (to the stratum granulosum) have been reported in studies, utilizing methylene blue or silver stainings (Woolard 1935). In the beginnings of ultrastructural examination, numerous reports on the electron microscopic image of the skin receptors appeared (Halata 1975; Andres and von Düring 1973; Cauna 1973, 1980; Chouchkov 1978; Kruger et al. Even in recent papers (Kruger 1996; Kruger and Halata 1996; Messlinger 1996; Kruger et al. As the axon-Schwann cell complex approaches the basal epidermis, the thin Schwann cell basal lamina merges with the thicker epidermal basal lamina. The axon pene- trating the epidermis is accompanied by thin Schwann cell processes which follow its course until a single axonal proﬁle is completely enveloped by keratinocytes, without junctional specializations (Kruger et al. In the Meissner corpuscles of glabrous skin of monkey digits they found that the Aα-β-ﬁbers are closely intertwined with endings of peptidergic C-ﬁbers (SP and CGRP). These intertwined endings are segregated into zones containing nonpeptidergic C-ﬁbers expressing immunoreactivity for vanilloid receptor 1. The enormous number of free nerve endings in the cornea and the lack of any encapsulated receptors were demonstrated by Ramon y Cajal as early as 1909. The innervation density is 300–600 times that of the skin (Rozsa and Beuerman 1982). The number of PA neurons in the TG, that send their peripheral processes in the ophthalmic nerve is modest (La Vail et al. Both myelinated Aδ and unmyelinated C-ﬁbers are present in the peripheral cornea but the cen- tral cornea is innervated by unmyelinated ﬁbers. The latter penetrate Bowman’s membrane and terminate between the epithelial cells (Müller et al. Human premolars receive about 2,300 axons at the root apex, and 87% of these ﬁbers are unmyelinated. Most apical myelinated axons are fast conducting Aδ- ﬁbers with their receptive ﬁelds located at the pulpal periphery and inner dentin. These ﬁbers are probably activated by a hydrodynamic mechanism and conduct impulses that are perceived as a short, well-localized sharp pain. Most C-ﬁbers are slow-conducting ﬁne afferents with their receptive ﬁelds located in the pulp and transmit impulses that are experienced as dull, poorly localized and lingering pain (Nair 1995; Waite and Ashwell 2004). Free nerve endings in mature teeth are found in the peripheral plexus of Rashkow, the odontoblastic layer, the predentin, and the dentin. The endings are most numerous in the regions near the tip of the pulp horn, where more than 40% of the dentinal tubules can be innervated (Byers 1984). Endings can extend for up to 200 µm into the dentinal tubules in both monkey and human teeth, particularly near the cusps of the crown (Byers and Dong 1983; Waite and Ashwell 2004). The periodontal pain is usually well localized and exacerbated by pressure (Waite and Ashwell 2004). In the muscles, the free nerve endings are found in the adventitia of the blood vessels,butalsobetweenmuscleﬁbers,intheconnectivetissueofthemuscleandin the tendons (Andres et al. The small myelinated afferent ﬁbers in the muscles have conduction velocities from 2. Of all of the small myelinated and unmyelinated ﬁbers, approximately 40% were believed to be nociceptors (Marchettini et al. Bone has a rich sensory innervation; the density of nociceptors in the periosteum is high, whereas nerve ﬁbers in the mineralized portion of the bone are less concentrated and are associated with blood vessels in Volkman and Haversian canals (Bjurholm et al. Nociceptors in the joint are located in the capsule, ligaments, bone, articular fat pads, and perivascular sites, but not in the joint cartilage (Heppelmann et al. The free nerve endings in the cruciate ligaments are found subsynovially, and are seen also between collagen ﬁbers, close to blood vessels. However, at least part of the latter ﬁbers appear to be efferent sympathetic ﬁbers and not nociceptors (Halata et al. The branched, terminal tree of the unmyelinated ﬁbers has a "string of beads" appearance which probably represent multiple receptive sites in the nerve ending (Heppelmann et al. In the healthy back, only the outer third of the annulus ﬁbrosus of the inter- vertebral disk is innervated (see Coppes et al. Lower back pain was studied in diseased lumbar intervertebral discs and was for the ﬁrst time reported to be related to ingrowth of nociceptive ﬁbers by Coppes et al. This ﬁnding was conﬁrmed in 46 samples of diseased inter- vertebral disks (Freemont et al. Both groups characterized this ingrowth and extension of the neuronal disk network by the nociceptive neurotransmitter substance P. It is now well established that a change of the innervation of the disk is the morphological substrate for discogenic pain. The ﬁrst class is composed of "high-threshold" receptors that respond to mechanical stimuli within the noxious range. Such are found within different organs: gastrointestinal tract, lungs, ureters and urinary bladder, and heart (Cervero 1996; Gebhart 1996). The second class has a low threshold to natural stimuli and encodes the stimulus intensity in the magnitude of their discharges: "intensity-encoding" receptors. The cardiac receptors are the peripheral processes of the pseudounipolar PA neurons, located in the SG and the ganglion inferius n. The sympathetic afferents are considered solely responsible for the conduction of pain arising in the heart. However, Meller and Gebhart (1992) suggest that afferent ﬁbers of the vagus nerve might also contribute to the cardiac pain.
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There is one prospective cohort level II study (moderate evidence) of neuroimaging in temporal lobe epilepsy of childhood (33) order 500 mg meldonium with visa. Sixty-three children with new-onset temporal lobe epilepsy were included; MRI was performed in 58 (92%) and CT in 48 (76%) cheap 500 mg meldonium mastercard. Computed tomography was Chapter 11 Neuroimaging of Seizures 203 positive in 23% of cases, which included all tumors, but failed to detect cases of HS. Computed tomography demonstrated calciﬁcations in the posterior area of the hippocampus in one case that was not detected on MR. The authors proposed three groups to classify partial seizures based on the relationship among neuroimaging ﬁndings, prior history, and age: Group I: Developmental temporal lobe epilepsy (10 patients). This epilepsy is associated with tumors and malformations that are usually long-standing and nonprogressive cortical lesions such as gangliogliomas, dysembryoplastic neuroepithe- lial tumors, and pilocytic xanthochromic astrocytomas. Group II: Temporal lobe epilepsy with hippocampal sclerosis (18 patients), included children with signiﬁcant prior clinical history of neurologic insult, including complicated febrile seizures, hypoxic-ischemic encepha- lopathy, and meningitis. Group III: Cryptogenic temporal lobe epilepsy (34 patients) in whom no etiology could be determined. Fifty patients had neuroimaging abnormal- ities and 36 had abnormal clinical ﬁndings. The neurologic exam ﬁndings of hemiparesis, mental retardation, and neurocutaneous stigmata were risk factors in predicting abnormal neuroimaging ﬁndings. However, the abnormality detected on neurologic examination or the type of seizure was not a predictive parameter in determining tumor resectability as shown by neuroimaging. A level III study (limited evidence) by Berg and coworkers (35) reported the neuroimaging ﬁndings in a group of 613 children with newly diag- nosed temporal lobe epilepsy. The strongest predictor of abnormal imaging was an abnormal motor exami- nation (odds ratio: 18. The MR ﬁndings in 186 of 274 consecutive patients who underwent temporal lobectomy for intractable epilepsy were retrospectively reviewed (moderate evidence) (Table 11. MRI sensitivity and speciﬁcity in temporal lobe epilepsy Item Sensitivity (%) Speciﬁcity (%) Reference Hippocampal lesion 93 83 Lee et al. Magnetic resonance imaging detected 121 hippocampal/amygdala abnormalities (sensitivity and speciﬁcity of 93% and 83%, respectively) and 60 other abnormalities in the remainder of the temporal lobe (sensitivity and speciﬁcity of 97% and 97%, respectively). Increased signal of the hippocampus on T2-weighted images had a sensi- tivity of 93% and speciﬁcity of 74% in predicting mesial temporal sclero- sis (Fig. Forty-two temporal tumors were detected with a sensitivity and speciﬁcity of 83 and 97%, respectively. The sensitivity of CT and MRI in temporal lobe pathology was recently reported by Sinclair et al. All patients underwent temporal lobectomy for intractable epilepsy, hence providing histopathology as the reference stan- dard. Magnetic resonance imaging found abnormalities in 27 cases (64%) and CT scan in 12 of 39 cases (31%). Magnetic resonance imaging was clearly more sensitive than CT in the detection of pathology. The MRI sensitivity in demonstrating the epileptogenic zone determined by EEG (a weak standard reference) was investigated in a level III study (limited evidence). The weakness of the reference standard is in part com- pensated by the number of cases. Pooled data of 809 patients, of whom 370 had temporal lobe abnormalities, were analyzed (38). The sensitivity of MR was 55% for temporal epileptogenic zones and 43% for extratemporal regions as determined by EEG. They studied 207 patients referred for hearing loss with high-resolution MR and found two cases of unsuspected HS. The image corresponds to a patient with intractable epilepsy and EEG ﬁndings of left temporal origin. Coronal image at the level of the temporal lobes demonstrates left hip- pocampal sclerosis characterized by reduction in size, and increased signal intensity (arrows), compared to the normal right hippocampus. MRI sensitivity and speciﬁcity for hippocampal sclerosis Author Patients Sensitivity Speciﬁcity Comments Spencer, 153 71? FLAIR sequence was 1996 (43) compared to SE (91% sensitivity) patients had seizures. One of them had seizure onset 18 months prior to the MR study that was believed to be associated with hemorrhage from an arteriovenous malformation ipsilateral to the HS. The most important neuroimaging ﬁndings in HS are small size (atrophy) and intense T2 signal of the hippocampus (Table 11. These signs have been quantiﬁed in a level III retrospective study (limited evi- dence) of 41 MRI of patients who underwent temporal lobectomy (40). The authors compared measurements of the left and right hippocampal for- mations and found them to have 76% sensitivity and 100% speciﬁcity for correct seizure lateralization. All 17 patients with HS had reduced absolute hippocampal volumes, greater than 2 standard deviations (SD) below the mean of the control group. The degree of reduced hippocampal size correlates well with the severity of the HS. Hippocampal volumes were within normal range in all patients with generalized epilepsy, and in extratemporal and extrahippocampal temporal lesions.
The SPECT studies generally show patchy perfusion deﬁcits cheap meldonium 250mg with visa, often in areas with no visible injury on CT generic meldonium 250mg. One of the largest studies, although retrospective, was performed by Abdel- Dayem and colleagues (56) (moderate evidence), who reviewed SPECT ﬁndings in 228 subjects with mild or moderate TBI. Stamatakis and colleagues (57) (moderate evidence) studied 61 patients with SPECT and MRI, within 2 to 18 days after injury, and found that SPECT detected more extensive abnormality than MRI in acute and follow-up studies. A small study (limited evidence) of patients with persistent postconcussion syndrome after mild TBI found that SPECT showed abnormalities in 53% of patients, whereas MRI and CT showed abnormalities in only 9% and 4. Positron emission tomography (PET) can measure regional glucose and oxygen utilization, CBF at rest, and CBF changes related to performances of different tasks. A few PET studies have reported various areas of decreased glucose utilization, even without visible injury. Bergsneider and colleagues (59) (limited to moder- ate evidence) prospectively studied 56 patients with mild to severe TBI, 242 K. The authors state in this and previous reports that TBI patients demonstrate a triphasic pattern of glucose metabolism changes that consist of early hyperglycolysis, fol- lowed by metabolic depression, and subsequent metabolic recovery (after several weeks). There are few small studies evaluating sensitivity of xenon CT and even fewer describing the sensitivity of functional MRI (fMRI) or MR perfusion. Predictor variables may not be as accurate if measured too early, but may be less useful if measured too late. Evaluation of prognostic vari- ables has ranged from studying individual measures to comprehensive multimodal evaluations. Many clinical predictors have been studied including age, gender, GCS, pupillary reactivity, intracranial pressure (ICP), coagulopathy, hypothermia, hypoxia, hypotension, hyperglycemia, and electrolyte imbalance, in addition to imaging ﬁndings. Thatcher and colleagues (60) (moderate evidence) studied 162 patients and showed that combined measures are more reliable and accurate than any single measure. There have been relatively few comprehensive studies of long- term prognostic indices compared to acute prognostic indices (e. Analysis of CT predictors of outcome have yielded variable results in the literature. Abnormalities found on CT have been analyzed individu- ally, collectively (in various combinations), or combined with clinical prog- nostic variables. Various studies have shown improvement in outcome prediction after severe TBI when adding CT information to clinical vari- ables (moderate evidence). Computed tomography has been studied more extensively than other imaging modalities, although it is likely that MRI and other imaging methods will have greater value for predicting long- term outcome. Supporting Evidence: Early research on CT predictors was performed with older technology that was less sensitive to the presence of injuries. Many studies used a crude categorization system, with limited informa- tion regarding the degree of abnormalities. Others have attempted to assess outcome prediction using more detailed classiﬁcation schemes. Accord- ingly, there has been variability in the reported predictors and success at prediction. Imaging Classiﬁcation Schemes Although there are a variety of classiﬁcation schemes, very few have been used to predict clinical outcomes. The most widely studied classiﬁcation scheme is based on CT ﬁndings in the Trauma Coma Databank (TCDB), developed by Marshall and colleagues (61), based on the status of cisterns, midline shift, and mass lesions. Categories include (a) diffuse injury I (normal): no visible intracranial pathology; (b) diffuse injury II (small Chapter 13 Neuroimaging for Traumatic Brain Injury 243 lesions): cisterns are present, midline shift <5mm, no lesions greater than 25cc; (c) diffuse injury III (swelling): cisterns are compressed, midline shift <5mm, no lesions greater than 25cc; (d) diffuse injury IV (shift): midline shift of >5mm, no lesions greater than 25cc; (e) any surgically evacuated lesion; and (f) any nonevacuated mass lesion greater than 25cc. The TCDB classiﬁcation was developed in severely injured patients (GCS <8) and ini- tially compared to discharge outcomes, although it has more recently been validated using 3- and 6-month GOS (62). It is reasonably good at pre- dicting mortality, but it may not be as applicable to mild/moderately injured patients and has been criticized as poorly predictive of functional recovery (63). The TCDB classiﬁcation has been variously modiﬁed, often to include the type, number (31,64), or location of lesions (65). In the AANS guideline (24), an extensive review of the previous CT literature (strong evidence) showed that the TCDB CT classiﬁcation scheme strongly corre- lated with outcome. Normal Scans Extensive review (strong evidence) shows that normal CT scans in severe TBI patients are predictive of favorable outcome (61% to 78. In a recent study (moderate evidence) normal CT scans in moderate/severe TBI patients were associated with better neu- ropsychological performance at 6 months (66). Brain Swelling Brain swelling is a subjective ﬁnding and more difﬁcult to evaluate as an outcome predictor. Partly compressed ventricles and cisterns are not as reliably measured as obliterated ventricles and cisterns (67). Marshall and colleagues (61) (strong evidence) studied the TCDB classiﬁcation in 746 patients and reported that brain swelling on CT (categorized by diffuse injury III) was predictive of mortality, and that survivors showed a trend of worse GOS associated with increasing grade of diffuse injury. Com- pressed basal cisterns have been associated with a threefold risk of raised ICP, and a two- to threefold increase in mortality (24). However, brain swelling on CT does not appear to correlate with neuropsychological outcomes (14) (moderate evidence). Midline Shift Midline shift is felt to be less important than other CT parameters for pre- dicting mortality or GOS score (24). However, some investigators have shown that midline shift may be predictive of worse outcomes based on rehabilitation measures such as greater need for assistance with ambula- tion, activities of daily living (ADLs), and supervision at rehabilitation discharge (68). Hemorrhage The presence of hemorrhage has different prognostic signiﬁcance depend- ing on the extent and location of blood. Traumatic subarachnoid hemor- rhage is a signiﬁcant independent prognostic indicator (24,69) (strong evidence), associated with a twofold increase in mortality, and a 70% pos- itive predictive value for unfavorable outcome (24). Hematoma volume correlates with outcome, and has 78% to 79% positive predictive value for unfavorable outcome (24). Another study (moderate evidence) found that patients with combined SDH and ICH on CT had poor outcome even after surgery compared to those with EDH or ICH alone (70).
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